Is C6 p.Arg182Trp (c.544C>T) pathogenic?

C6 p.Arg182Trp (c.544C>T) is classified Uncertain significance in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely benign (0.1686); Ultra-rare (popmax 0.09%, amr).

How common is C6 p.Arg182Trp (c.544C>T) in the general population?

C6 p.Arg182Trp (c.544C>T) is ultra-rare (popmax 0.09%, amr) (gnomAD).

What do computational predictors say about C6 p.Arg182Trp (c.544C>T)?

AlphaMissense predicts likely benign (score 0.1686) — an in-silico prediction, not a clinical call.

C6 p.Arg182Trp

c.544C>T · rs141862960 · VCV1035557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.09%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1686	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -10.39	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.21	donor loss, 43 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.1	GERP -1.2, phastCons 0.024
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.09% Admixed American · 54/59,986 alleles

Filtering AF 0.0709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0639%

Overall 0.00725% 117/1,613,818 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.09%	1,111
Remaining individualsnot grpmax-eligible	0.0192%	5,208
Middle Eastern	0.0165%	6,060
South Asian	0.00549%	18,217
African / African-American	0.00533%	18,751
European (non-Finnish)	0.00339%	29,496
East Asian	0.00223%	44,858

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: C6
Protein: p.Arg182Trp
Coding: c.544C>T
MANE Select: NM_000065
dbSNP: rs141862960
Type: single nucleotide variant
Location: chr5:41195835 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 182: a disulfide bond; the macpf domain; a β-strand

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C6 p.Arg182Gln Uncertain significance ★★ ⚠ same residue
C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Arg606Ter Pathogenic ★★ same type
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same type
C6 p.Ala21Val Uncertain significance ★★ ⚠ same type
C6 p.Ala396Gly Uncertain significance ★★ ⚠ same type
C6 p.Ala456Thr Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/c6-p-arg182trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown